Stroke is defined as an acute focal neurological deficit resulting from a cerebrovascular disease. The two main types of stroke are ischemic and hemorrhagic, accounting for approximately 85% and 15%, respectively (Hickey 2003. The clinical practice of neurological and neurosurgical nursing (5th ed.). Philadelphia: Lippincott, Williams & Wilkins). When an ischemic stroke occurs, the blood supply to the brain is interrupted and brain cells are deprived of glucose and oxygen. Approximately 45% of ischemic strokes are caused by small or large artery thrombus, 20% are embolic origin, and others have an unknown cause (Hickey 2003. The clinical practice of neurological and neurosurgical nursing (5th ed.). Philadelphia: Lippincott, Williams & Wilkins).
Transient ischemic attack (TIA) (also known as “mini-stroke”) is defined on tissue-based characteristics as a transient episode of neurological dysfunction caused by focal brain, spinal cord or retinal ischemia, without acute infarction (Easton et al. 2009. Stroke 40: 2276-93). TIA is further characterized by a sudden onset of neurological symptoms that resolve completely within 24 hours. TIA may be reported in 0.5% to 8% of the elderly population (Bots et al., 1997. Stroke 28(4): 768-73). A patient with a TIA is at high risk of subsequent adverse events. The 90-day risk of stroke has been reported to be greater than 10%, with the highest risk occurring within the first 2 days (Johnston et al., 2003. Neurology 60: 1429-34).
Stroke is one of the most important vascular diseases. Stroke remains the second leading cause of death worldwide and is one of the main causes of adult disability and early invalidity in Europe (Murray and Lopez, 1997. Lancet 349: 1269-76; Murray and Lopez 1997. Lancet 349:1498-504). In the US, more than 700 000 people have a stroke each year whereof 550,000 are first strokes (Thom et al. 2006. Circulation 113: 85-151). Therefore, it is an important public health problem and a burden to health care providers and to the community at large because of the amount of effort that has to be invested in the planning and provision of health care.
The incidence of stroke increases markedly with increasing age in our society (Madan and Wagener, 1992. Stroke 23:1230-36). Most ischemic strokes occur between the ages of 71 and 80 years while most hemorrhagic strokes appear between 60 and 70 years (Colombo et al., 1989. Rivista de Neurologia 59: 1-7).
Prognosis of the outcome for stroke patients after a defined interval can either be functional or related to individual survival. For functional outcome prognosis, the morbidity of a patient after a defined time is determined using a score system such as the “modified Ranking Scale” (mRS; Bonita and Beaglehole, 1988. Stroke 19: 1497-1500) or the “National Institutes of Health Stroke Scale” (NIHSS; Adams et al., 1999. Neurology 53: 126-31). The NIHSS is currently considered the “gold standard”. The functional outcome may also be expressed in terms of need of nursing care or with respect to activities of daily living (ADL), e.g. according to the Barthel Index and Ranking Scale (Collin et al., 1988. International Disability Study 10: 61-3; Bonita and Beaglehole, 1988. Stroke 19: 1497-1500).
The prognosis of stroke mainly depends on the incidence of complications (Davenport et al. 1996. Stroke 27: 415-20; Johnston et al. 1998. Stroke 29: 447-53). Infections, especially pneumonias, are the third most common stroke complication (Langhorne et al. 2000. Stroke 31: 1223-9; Katzan et al. 2003. Neurology 60: 620-5) and thought to be the most common cause of poor outcome and death in stroke patients (Henon et al. 1995. Stroke 26: 392-8; Hilker et al. 2003. Stroke 34: 975-81; Heuschmann et al. 2004. Arch Intern Med 164: 1761-8). The frequency of infections in acute stroke patients is very high: 21-65% of patients with an acute stroke develop infections and 10-22% develop pneumonias (Castillo et al. 1998. Stroke 29: 2455-60; Davenport et al. 1996. Stroke 27: 415-20; Georgilis et al. 1999. J Int Med 246: 203-9; Grau et al. 1999. J Neurol Sci 171: 115-20; Johnston et al. 1998. Stroke 29: 447-53; Langhorne et al. 2000. Stroke 31: 1223-9), compared to the incidence of nosocomial or healthcare associated infections occurring in an average of 7-10% of all patients (Bucher et al. 2000. Tidsskr Nor Laegeforen 120: 472-5) and about 3% in postoperative patients (Smyth and Emmerson 2000. J Hasp Infect 45: 173-84). It was shown that the risk of infection is highest in the acute state of stroke at the first and second day after stroke (Grau et al. 1999. J Neural Sci 171: 115-20; Kong et al. 1998. Arch Phys Med Rehabil 79: 1535-9). The high incidence of infections in stroke patients is likely to be the result of an impaired immune function (Livingston et al. 1988. Arch Surg 123: 1309-12; Woiciechowsky et al. 1998. Nat Med 4: 808-13; Dirnagl et al. 2007. Stroke 38: 770-3). Immunodepression after stroke can be detected within a few hours after induction of ischemia and may last for several weeks (Dirnagl et al. 2007. Stroke 38: 770-3). Several risk factors contribute to the increased susceptibility of stroke patients for infections: aspiration due to drowsiness, impaired bulbar reflexes, dysphagia, and hypostasis in bed-ridden patients, as well as the need for invasive medical procedures (Perry and Love 2001. Dysphagia 16: 7-18).
Post-stroke infection can also affect patients with TIA and is most likely, such as acute ischemic and hemorrhagic stroke, associated with a poor short-term outcome (Kwan and Hand 2007. Acta Neural Scand 115:331-8).
It is well known that stroke produces an inflammatory response with an increase of white blood cell (WBC) count in peripheral blood (Kazmierski et al. 2001. Wiad Lek 54:143-51) as well as body core temperature (Boysen and Christensen 2001. Stroke 32:413-7), brain temperature (Schwab et al. 1997. Neurology 48:762-7) and C-reactive protein (CRP) (Idicula et al. 2009. BMC Neurology 9:18). However, the systemic inflammatory response after stroke may rather result from a response to the necrotic tissue itself than from an infection. Necrotic tissue is eliminated by cellular, humoral, and metabolic mechanisms, which are all part of the inflammatory reaction (Kogure et al. 1996. Acta Neurochir Suppl (Wien) 66:40-3). The increase in body temperature starts within 24 hours of the event, whereas fever due to infection seems to have a later onset (Boysen and Christensen 2001. Stroke 32:413-7; Davalos et al. 1997. Cerebrovasc Dis 7:64-9; Castillo et al. 1999. Cerebrovasc Dis 9:22-7; Castillo et al. 1998. Stroke 29:2455-60). In ischemic stroke patients without evidence of infection, the elevation of body temperature and WBC as well as CRP was significantly correlated with lesion volume and initial stroke severity (Audebert et al. 2004. Stroke 35: 2128-2133). Moreover, the systemic inflammatory response was shown to be attenuated by a successful thrombolysis therapy. Thus, the induced rescue of brain tissue may be a result of reduced systemic inflammation by avoiding cerebral necrosis.
Procalcitonin (PCT) has become a well-established biomarker for the diagnosis of sepsis. PCT reflects the severity of a bacterial infection and is in particular used to monitor progression of infection into sepsis, severe sepsis, or septic shock. It is possible to use PCT to measure the activity of the systemic inflammatory response, to control success of therapy, and to estimate prognosis (Assicot et al. 1993. Lancet 341:515-8; Clec'h C et al. 2004. Crit. Care Med 32:1166-9; Lee et al. 2004. Yonsei Med J 45:29-37; Meisner et al. 2005, Curr Opin Crit. Care 11:473-480; Wunder et al. 2004. Inflamm Res 53: 158-163). The increase of PCT levels in patients with sepsis correlates with mortality (Oberhoffer et al. 1999. Clin Chem Lab Med 37:363-368).
PCT has already been used for therapy guidance of antibiotics, but not after an acute stoke. In patients representing at the emergency department with symptoms of lower respiratory tract infections, PCT was measured and only patients with PCT concentrations>0.25 ng/mL or >0.5 ng/mL were treated with antibiotics (Christ-Crain et al. 2004. Lancet 363:600-7). In patients with community-acquired pneumonia (CAP) antibiotic treatment was based on serum PCT concentrations (strongly discouraged at PCT concentrations<0.1 ng/mL; discouraged at PCT concentrations<0.25 ng/mL; encouraged at PCT concentrations>0.25 ng/mL, and strongly encouraged at PCT concentrations>0.5 ng/mL) (Christ-Crain et al. 2006. Am J Resp Crit. Care Med 174:84-93). PCT guidance substantially reduced antibiotic use in CAP without deterioration of patients outcome. Similarly, PCT-guided therapy using the same decision thresholds as described above, also markedly reduced antibiotic use for acute respiratory tract infections in primary care without compromising patients outcome (Brief et al. 2008. Arch Intern Med 168:2000-7).
Current guidelines on acute stroke management advise against prophylactic administration of antibiotics (Hacke et al. 2003. Cerebrovasc Dis 16: 311-37). Moreover, a randomized clinical trial of antibiotic prophylaxis recently provided evidence-based support to this recommendation, as it showed that intravenous administration of levofloxacin was not better than placebo to prevent infections in patients with acute stroke (Chamorro et al. 2005. Stroke 36: 1495-500). In contrast, in patients with acute severe stroke (mRS>3), administration of mezlocillin plus sulbactam lowered the rate of infection and may be associated with a better clinical outcome (Schwarz et al. 2008. Stroke 39: 1220-7). However, with regard to the development of possible resistance to antibiotics as well as antibiotic induced side effects, a prophylactic treatment of patients with an acute stroke is not considered to be appropriate and current guidelines on acute stroke management advise against prophylactic administration of antibiotics (Hacke et al. 2003. Cerebrovasc Dis 16: 311-37; Ringleb et al. 2008. Cerebrovasc Dis 25: 457-507).
Against the background of impaired immune function in stroke patients on the one hand and the systemic inflammatory response after stroke on the other hand, it is absolutely unclear whether PCT concentrations are changed in patients with post-stroke infections. An investigation of serum PCT levels in patients suffering from an acute stroke did not reveal significant differences between the day of hospitalization and day 7 (Miyakis et al. 2004. Clin Chim Acta 350: 437-9). No correlation of PCT levels with mortality or neurological outcome has been found in this study. Molnar and colleagues measured PCT in serum of patients with acute ischemic stroke and TIA (Molnar et al. 2008 J Clin Pathol 61: 1209-13). Although PCT was measured serially, the authors did not find any difference in PCT levels measured at different time points after stroke, except that a slight increase of PCT at 72 hours indicated subsequent post-stroke infections. The results of both studies could be attributed; to the respective PCT test systems used, namely the PCT LIA in Miyakis et al. with a functional assay sensitivity (FAS) of 0.08 ng/mL and the PCT Kryptor in Molnar et al. with a FAS of 0.06 ng/mL.
Vogelgesang et al. measured PCT values in serum of patients with stroke on days 7 and 14 after patients admission to the hospital as one out of three criteria for infection using a cut-off for PCT of >0.5 ng/mL (Vogelgesang et al. 2008. Stroke 39: 237-41).
A diagnostic method to determine the etiology of inflammatory processes by determining the concentration of PCT and to ascertain from the presence or absence of the peptide whether the inflammation is of infectious or non-infectious etiology is described in EP 0 80 702 B1.
A method for the prognosis of an outcome or assessing the risk of a patient having suffered a stroke or transient ischemic attack by determining the level of PCT is described in EP 08167512.6 and EP 08168671.9.
A method for the prognosis for a patient having a primary non-infectious disease by determining the level of PCT and correlating the PCT level to a risk of the patient to contract a further disease or medical condition which has not yet been manifested and/or is not yet symptomatic, is described in EP 07015271.5.
Regarding the high incidence of post-stroke infections and its association of a poorer outcome of stroke or TIA patients suffering a post-stroke/post-TIA infection, these patients should be closely monitored for infection.
Thus, the inventors of the present invention have investigated whether measurement of Procalcitonin levels in a sample of a bodily fluid from a patient who suffered from an acute ischemic or hemorrhagic stroke or a transient ischemic attack could be used for the diagnosis and treatment guidance of a post-stroke/post-TIA bacterial infection in these patients.